One-pot, three-component synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines catalyzed by ytterbium triflate

Article abstract of DOI:10.1016/j.tetlet.2011.12.121

A straightforward method has been developed for the synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines by Yb(OTf)₃ catalyzed three-component reaction of aldehydes, acetamide, and imidazo[1,2-a]pyridines. A series of substituted 3-substituted im

Full text of DOI:10.1016/j.tetlet.2011.12.121

Tetrahedron Letters 53 (2012) 1253–1257
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Tetrahedron Letters
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One-pot, three-component synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines
catalyzed by ytterbium triflate
⇑
Kasiviswanadharaju Pericherla, Bharti Khungar, Anil Kumar
Department of Chemistry, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A straightforward method has been developed for the synthesis of 1-amidomethyl-imidazo[1,2-a]pyri-
dines by Yb(OTf)3 catalyzed three-component reaction of aldehydes, acetamide, and imidazo[1,2-a]pyr-
idines. A series of substituted 3-substituted imidazo[1,2-a]pyridines were synthesized in moderate to
good yield (21–74%) under mild reaction condition and the catalyst was recycled for four cycles.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 17 November 2011
Revised 27 December 2011
Accepted 28 December 2011
Available online 5 January 2012
Keywords:
Imidazo[1,2-a]pyridines
1-Amidomethyl-imidazo[1,2-a]pyridines
Multicomponent reaction
One-pot
Ytterbium triflates
Imidazo[1,2-a]pyridines are important biologically and phar-
maceutically active heterocyclic compounds. They have received
considerable attention in the field of pharmaceutical industry ow-
ing to their broad range of biological activities. Imidazo[1,2-a]pyr-
idine derivatives have been studied for different therapeutic
classes such as antifungal,1 antibacterial,2 antiviral,3 anti-rhinovi-
ral,4 CDK inhibition,5 aromatase inhibition,6 K+-stimulated ATPase
inhibition,7 ligands for peripheral benzodiazepine (PBD) recep-
tors,8 and b-amyloid (Ab) aggregate,9 bradykinin B2 receptor
antagonists.10 Imidazo[1,2-a]pyridine nucleus is also core struc-
ture of several drug formulations such as alpidem, nicopidem, sar-
ipidem, zolimidine, zolpidem, and olprinone, which are presently
available in market (Fig. 1).
In recent years multicomponent reactions (MCR) have emerged
as a powerful tool in combinatorial chemistry for diversity oriented
synthesis of small sized organic compounds of pharmaceutical
interest.11 These reactions offer significant advantages over lin-
ear-type conventional synthesis. They retain majority of the atoms
of starting materials and thus provide high atom economy and E
factor. In addition to the low cost, reduction in overall reaction
time and operational simplicity are the other advantages of MCR.
Over the past decades, rare earth metals have been used in the
diversity of organic transformations as catalysts, especially lantha-
nide triflates function as efficient Lewis acid catalysts.12 Moisture
insensitiveness, stability, high catalytic activity, and reusability
without much loss of activity are distinctive features of metal tri-
flates. From environmental and efficiency point of view lanthanide
triflates have become highly attractive Lewis acid catalysts for var-
ious chemical reactions. In continuation of our efforts to develop
13
novel reaction methodologies using Yb(OTf)3 herein, we report
a
straightforward and practical Yb(OTf)3 catalyzed one-pot,
three-component method for the synthesis of 1-amidomethyl-imi-
dazo[1,2-a]pyridines (Scheme 1). Recently, Chaubet et al. have re-
ported the synthesis of polysubstituted 2-amino-1,3-thiazoles via
tandem aza-Friedel–Crafts reaction/Hantzsch cyclization.14 They
have achieved N-[(aryl)(2-alkyl/arylimidazo[1,2-a]pyridin-3-yl)-
methyl]thiourea via multicomponent reaction of 2-methylimi-
dazo[1,2-a]pyridine, aldehyde and thiourea using TiCl4 or thia-
mineꢀHCl as catalyst. To the best of our knowledge, this is the
first report on one-pot synthesis 1-amidomethyl-imidazo[1,2-
a]pyridines (4).
Synthesis of imidazo[1,2-a]pyridine derivatives (1a–e) was
achieved by reacting appropriately substituted a-bromoacetophe-
none with 2-aminopyridines.15 To optimize the reaction conditions
for the synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines (4),
initially we attempted condensation of 2-p-tolyl-1H-imidazo[1,2-
a]pyridine (1a), 4-chloro-benzaldehyde (2a0), and acetamide (3)
using various solvents in the presence of Yb(OTf)3 (Table 1). Two
new spots were observed on TLC and the ratio of these spots varied
with solvents (Table 1). From 1H & 13C NMR, IR, and mass data, it
was clear that polar spot (by TLC) is expected N-((4-chloro-
phenyl)(2-p-toly-lH-imidazo[1,2-a]pyridin-3-yl)methyl)acetamide
(4aa0) and non polar one is bis(imidazo[1,2-a]pyridine) (5aa0).
The structure of (4aa0) and 5aa0 was confirmed by 1H NMR, 13
NMR, and mass data. The ESI-MS spectrum of 4aa0 displayed a peak
C
⇑
Corresponding author.
E-mail address: anilkadian@gmail.com (A. Kumar).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.121

1254
K. Pericherla et al. / Tetrahedron Letters 53 (2012) 1253–1257
Table 2
CN
N
N
N
N
Optimization of different catalystsa
Cl
O
HN
CH3
N
N
Cl
H3C
Sr. No.
Catalyst
Catalyst (mol %)
Time (h)
Yieldb (%)
O
O
CH3
c
N
1
2
3
4
5
6
7
8
9
—
—
24
12
12
12
15
15
12
15
15
15
15
15
—
N
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Mont. K-10
AgOTf
20
10
5
72
54
45
28
46
65
36
24
34
25
54
Zolpidem
Alpidem
Olprinone
Figure 1. Structure of some imidazo[1,2-a] pyridine drug molecules.
5
20
20
20
20
20
20
20
p-TSA
R2
Cu(OTf)2
Sc(OTf)3
Er(OTf)3
Zn(OTf)2
La(OTf)3
R2
N
R1
N
10
11
12
N
R1
R
N
R
NH
Ar
1a-e
CH3
a
Reagents and conditions: 1a (1 equiv), 2a0 (1 equiv), 3 (1.5 equiv), 1,4-dioxane
O
+
(5 mL), 120 °C.
4aa'-ei'
+
b
Isolated yield.
No desired product formed.
R1
Yb(OTf)3, 1,4-dioxane
120 °C, 12 h
c
Ar-CHO
R2
2a'-i'
N
R
+
O
N
N
Ar
diethyl ether and thus we were not able to extract it from
[bmim][PF6]. We tried regular water/ethyl acetate work-up, but
[bmim][PF6] is soluble in ethyl acetate and not in water. Lastly,
we performed column chromatography of the reaction mass, but
in this case also we could not remove ionic liquid completely from
the product. Recrystallization using dichloromethane was found to
be good method for the removal of ionic liquid but recovery of the
product was low. Thus, we selected 1,4-dioxane as solvent of
choice for this reaction although it gave relatively lower yield of
4aa0 (72%) than that of [bmim][PF6].
R1
H3C
NH2
3
R
R2
N
5
1a R1 = CH3, R2 = R = H
2a' Ar = 4-ClC6H4
2f' Ar = 3-NO2C6H4
2g' Ar = 4-NO2C6H4
2h' Ar = 3-Indolyl
1b R1 = OCH3, R2 = R = H
1c R1 = H, R2 = NO2, R = H
1d R1 = Cl, R2 = H, R = H
1e R1 = Cl, R2 = H, R = Br
2b' Ar = 4-OCH3C6H4
2c' Ar = 3-OCH3C6H4
2d' Ar = 3-OCH3, 4-OCH3C6H3 2i' Ar = 2-Thiophenyl
2e' Ar = C6H5
Scheme 1. Synthesis of 1-amidomethylimidazo[1,2-a]pyridines (4) using Yb(OTf)3
To find the best catalyst, we screened the model reaction in 1,4-
dioxane at standardized condition using different acidic catalysts
(Table 2). While there was no conversion observed when the reac-
tion was performed without any catalyst (Table 2, entry 1), other
metal triflates such as AgOTf, Cu(OTf)2, Sc(OTf)3, Er(OTf)3, and
Zn(OTf)2 gave poor yield of 4aa0. It is worthy to mention that in
all the cases the reaction was incomplete with starting materials
remaining in the reaction mixture. Among all metal triflates,
Yb(OTf)3 gave highest yield of 4aa0 (72%) whereas p-TSA resulted
in 65% of 4aa0 among other acidic catalysts used (Table 2, entry
5). The high catalytic activity of Yb(OTf)3 could be explained by
the fact that Yb+3 is the hardest cation and therefore the most oxo-
philic, due to its smaller ionic radius, so it can coordinate with oxy-
gen atom of C@O group in aldehyde to make it more electrophilic,
leading to the enhancement of rate of reaction. The variation in the
loading of the catalyst also affected the yield of 4aa0. When 5, 10,
and 20 mol % of Yb(OTf)3 was used for the model reaction under
standardized reaction condition it resulted in 45%, 54%, and 72%
yields of 4aa0, respectively. Further increase in the catalyst loading
did not improve the yield of 4aa0.
In order to investigate the generality of the reaction, we applied
this strategy to various substrates having both electron donating
and electron withdrawing groups. The results are summarized in
Table 3. The substituent on C-2 phenyl ring of imidazo[1,2-a]pyri-
dine (1) has predominant effect on product formation. If the substi-
tuent is an electron releasing group it decreases the yield of 4 and
enhances the yield of 5. It may be due to the fact that presence of
electron rich aryl group at C-2 position increases electron density
on the imidazo[1,2-a]pyridine nucleus and makes it more nucleo-
philic to attack on intermediate 6. In contrast, when the substitu-
ent is an electron withdrawing group such as nitro, it gives
better yield of 4. This again may be due to decreased nucleophilic-
ity of the nucleus of imidazo[1,2-a]pyridine. Similarly, it was found
that aldehydes with electron donating groups resulted in lower
yields of 4 as compared to the aldehydes having electron with-
drawing groups.
as catalyst.
Table 1
Optimization of the reaction conditionsa
Entry
Solvent
Temp (°C)
Time (h)
Yieldb,c (%)
1
2
3
4
5
6
7
8
Toluene
DMF
H2O
1,4-Dioxane
1,4-Dioxane
[bmim][BF4]
[bmim][PF6]
[bmim][Br]
100
100
100
100
120
120
120
120
15
15
15
15
12
12
12
12
41 (30)
44 (25)
(10)d
56 (15)
72 (15)
27 (10)
75 (5)
28 (5)
a
Reagents and conditions: 1a (1 equiv), 2a0 (1 equiv), 3 (1.5 equiv), Yb(OTf)3
(20 mol %).
b
Isolated yield.
In parenthesis yield of bis(imidazo[1,2-a]pyridine).
No desired product formed.
c
d
at m/z 389.9 for [M+H]+ ion and a peak at 1682 cmꢁ1 was observed
for amidic C@O stretching in the IR spectrum. The 1H NMR spec-
trum contained a characteristic doublet at d ꢂ9.17 (d, J = 7.8 Hz,
1H) for amide –NH and a doublet at d ꢂ6.79 (d, J = 7.8 Hz, 1H)
for –CH attached to amide. A peak appeared at d 170.11 ppm in
13C NMR for C@O of acetamide group along with other carbons
of 4aa0 (see Supplementary data). These spectral data are consis-
1
tent with the structure of 4aa0. H NMR of compound 5aa0 con-
tained a characteristic singlet at d ꢂ6.65 ppm and displayed an
ion at m/z 539.2 for [M+H]+ ion in ESI-MS. These spectral data
are consistent with the structure of 5aa0.
To study the effect of solvent on the reaction, we performed the
model reaction in different solvents such as 1,4-dioxane, DMF, tol-
uene, water, [bmim][BF4], [bmim][PF6], and [bmim][Br]. Among all
solvents, [bmim][PF6] gave best yield of 4aa0 (75%) (Table 1, entry
7). The product was not soluble in non polar solvents such as

K. Pericherla et al. / Tetrahedron Letters 53 (2012) 1253–1257
1255
Table 3
Synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines using Yb(OTf)3
a,16
Entry
R1
R2
R
Ar
Productb (4)
% Yieldc
N
N
CH3
1
4-CH3
H
H
4-ClC6H4
NH
4aa0
4ab0
72d
CH3
O
N
Cl
CH3
N
NH
2
4-CH3
H
H
4-CH3OC6H4
36
CH3
O
H3CO
H3CO
N
CH3
N
3
4
4-CH3
4-CH3
H
H
H
H
3-CH3OC6H4
3-NO2C6H4
4ac0
4af0
33
28
NH
CH3
O
N
CH3
N
N
NH
O2N
CH3
OCH3
O
N
4ba0
4bb0
62
49
NH
5
6
4-OCH3
4-OCH3
H
H
H
H
4-ClC6H4
CH3
O
Cl
N
OCH3
N
NH
4-CH3OC6H4
CH3
O
H3CO
H3CO
N
OCH3
N
NH
7
8
4-OCH3
4-OCH3
H
H
H
H
3,4-(CH3O)2C6H3
4bd0
4be0
39
52
CH3
O
H3CO
N
N
OCH3
OCH3
C6H5
NH
CH3
CH3
O
N
N
NH
9
4-OCH3
H
H
H
3-NO2C6H4
4bf0
44
62
O
NO2
NO2
N
N
10
H
3-NO2
4-ClC6H4
4ca0
NH
CH3
O
Cl
NO2
N
N
11
H
3-NO2
H
4-CH3OC6H4
4cb0
59
NH
CH3
O
H3CO
(continued on next page)

1256
K. Pericherla et al. / Tetrahedron Letters 53 (2012) 1253–1257
Table 3 (continued)
Entry
R1
H
R2
R
Ar
Productb (4)
% Yieldc
NO2
N
N
12
13
3-NO2
H
C6H5
4ce0
55
NH
CH3
NO2
O
N
N
H
H
3-NO2
H
H
3-NO2C6H4
4cf0
74
65
NH
CH3
O
NO2
N
NO2
N
14
3-NO2
4-NO2C6H4
4cg0
NH
CH3
NO2
O
O2N
N
N
15
16
17
H
3-NO2
3-NO2
H
H
H
H
C8H5N
4ch0
39
29
40
NH
CH3
NO2
O
N
H
N
N
H
C4H3S
4ci0
NH
CH3
S
O
N
Cl
N
NH
4-Cl
3-NO2C6H4
4df0
CH3
O
NO2
N
Cl
N
Br
4ea0
4ef0
4eg0
46
30
21
NH
18
19
4-Cl
4-Cl
4-Cl
H
H
H
Br
Br
Br
4-ClC6H4
CH3
O
Cl
N
N
Cl
Cl
N
N
Br
3-NO2C6H4
NH
O2N
CH3
CH3
O
Br
NH
20
4-NO2C6H4
O
O2N
a
Reagents and conditions: compound 1 (1.0 equiv), 2 (1.0 equiv), 3 (1.5 equiv), 1,4-dioxane, 120 °C, 12 h.
All compounds showed satisfactory 1H NMR, 13C NMR and mass data.
Isolated yield.
b
c
d
Yields for four cycles were 72%, 69%, 68% & 66%, respectively.
As can be seen from Table 3, the method is applicable for differ-
because of the decreased nucleophilicity of imidazo[1,2-a]pyridine
nucleus due to the presence of bromo group. To further increase
the diversity in the product, we performed the reaction with
benzamide instead of acetamide but we did not observe the
desired product, instead bis(imidazo[1,2-a]pyridine) derivative
was observed, this may be because of poor nucleophilicity of benz-
amide compared to acetamide.
ent aromatic and heterocyclic aldehydes and substituted
imidazo[1,2-a]pyridines. It is also noteworthy to mention that
when 6-bromo-imidazo[1,2-a]pyridine was used, low yield of the
corresponding 3-substituted derivative of 4 was obtained (Table 3,
compare entries 17 & 19). However, there was no corresponding
bis(imidazo[1,2-a]pyridines) derivative in this case. This might be

K. Pericherla et al. / Tetrahedron Letters 53 (2012) 1253–1257
1257
δ
O
N
N
Yb(OTf)3
O
Ar
H
N
Yb(OTf)3
N
1
H
O
H
Ar
δ
N
OH
N
Ar
N
Ar
Yb(OTf)3
6
Yb(OTf)3
N
2
N
N
N
N
N
N
N
N
N
N
-OH-
+
H
Ar
O
NH
-Yb(OTf)3
Ar
Ar
Ar
Yb(OTf)3
NH2COCH3 (3)
CH3
O
7
4
5
Scheme 2. Plausible mechanism for synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines.
Based on the product distribution, a plausible reaction mecha-
nism is proposed in Scheme 2. It is expected that in the presence
of Lewis acid, aldehyde (1) gets activated and is attacked by imi-
dazo[1,2-a]pyridine at C-3 position to give aryl alcohol intermedi-
ate 6. Apparently, the C-3 position is the most electron-rich
position in imidazo[1,2-a]pyridine nucleus and thus electrophilic
substitution reaction takes place at this position selectively. This
intermediate 6 then generates an ion 7 by losing OH in presence
of Yb(OTf)3 which is then attacked by the nitrogen of acetamide
to give the desired product 4. However, if the intermediate 7 is at-
tacked by another molecule of imidazo[1,2-a]pyridine then it leads
to bis(imidazo[1,2-a]pyridine) derivative 5. To further confirm the
structure of 5 we reacted imidazo[1,2-a]pyridine (1a) and alde-
hyde (2a0) in the absence of acetamide under similar condition
and as expected we got the compound 5aa0.
We subsequently investigated the possibility of recycling of the
catalyst. After first cycle for model reaction, the product was ex-
tracted by ethyl acetate and Yb(OTf)3 was dried on rotatory evap-
orator under vacuum for subsequent reactions. The recovered
Yb(OTf)3 was charged with fresh lot of aldehyde, acetamide, imi-
dazopyridine, and the reaction was performed under same condi-
tions. After completion of reaction the product was extracted.
The above sequence was repeated four times to give 4a in good
yields (72%, 69%, 68% & 66%) without much loss in catalytic activity
of Yb(OTf)3.
In summary, we have developed a straightforward method for
the synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines by
Yb(OTf)3 catalyzed three-component reaction of aldehydes, acet-
amide, imidazopyridine. A series of 3-substituted imidazo[1,2-
a]pyridines have been synthesized in excellent yield (21–74%).
The catalyst can be recycled upto four cycles without much de-
crease in catalytic activity. Environment friendly catalyst and good
yield are the advantages of the method. To the best of our knowl-
edge this is the first report on synthesis of 1-amidomethyl-imi-
dazo[1,2-a]pyridines. We are evaluating c-Src kinase inhibition
and anticancer activity of 4, which will be published elsewhere.
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16. General procedure for the synthesis of 4: Ytterbium triflate (78 mg, 0.125 mmol,
20 mol %) was added to a 10 mL round bottom flask containing imidazo[1,2-
a]pyridine (1) (0.627 mmol, 1.0 equiv), aldehyde (2) (0.627 mmol, 1.0 equiv)
and acetamide (3) (56 mg, 0.940 mmol, 1.5 equiv) in 1,4-dioxane (3 mL). The
reaction mixture was stirred at 120 °C for 12 h. After completion of the
reaction, the reaction mixture was allowed to cool to room temperature and
the volatiles were evaporated. The residue was diluted with water (10 mL) and
extracted with ethyl acetate (2 ꢃ 10 mL). The combined organic layer was
dried over anhydrous sodium sulfate and evaporated to dryness. Crude
compound was purified by column chromatography using dichloromethane/
methanol (96:4 v/v) as eluent to get compound 4.
Acknowledgments
This work was financially supported by the University Grant
Commission (UGC), New Delhi. K.P. is thankful to BITS Pilani for re-
search fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.121.